Group IIA Secretory phospholipase (sPLA2-IIA) is known to be proinflammatory in vivo (Cirino, G., et al. (1994) J. Rheumatol. 21, 824–829), and concentration of this enzyme in serum and in tissues correlates with disease severity in several immune-mediated inflammatory pathologies in humans and rats. It is associated with the onset of rheumatoid arthritis (Jamal, O. S., et al. (1998) Ann. Rheum. Dis. 57, 550–558) and septic shock (Green, J.-A., et al. (1991) Inflammation 15, 355–367). Levels of sPLA2 in synovial fluid also correlate with severity of disease in rheumatoid arthritis patients (Lin, M. K. S., et al. (1996) J. Rheumatol. 23, 1162), and the concentration of PLA2-IIA increases in blood plasma in generalized inflammatory response resulting from infections, chronic inflammatory diseases, acute pancreatitis, trauma and surgical operations (Nevalainen, T. J., et al. (2000) Biochim. et Biophys. Acta. 1488 (1–2), 83–90). Hence, inhibition of PLA2 may logically, block the formation of a wide variety of secondary inflammatory mediators. The central role of PLA2 in inflammation thus makes the enzyme a potential target for drug development.
A number of studies have indicated that PLA2 and COX enzymes play an important role in the neurodegenerative processes associated with excitotoxic, ischemic, and traumatic brain injuries and neurodegenerative diseases (Palanas, A. M., et. al. (1995) Neurosci. Lett. 200, 187–190; Farooqui, A. A. et al. (1997) Neurochem. Int. 30, 517–522). In excitotoxic neuronal injury, levels of cytosolic phospholipase A2s (cPLA2s) is known to increase significantly (Sandhya, T. L. et al. (1998). Brain Res. 788, 223–231), and cPLA2 inhibitors have been shown to protect excitotoxic neuronal injury in hippocampal slice cultures (Lu, X.-R. et al. (2001). Free Rad. Biol. Med. 30, 1263–1273; Farooqui, A. A. et al. (1999). Brain Res. Bull. 49, 139–53). Besides cPLA2, sPLA2 has also been suggested to induce neuronal cell death via apoptosis which might be associated with arachidonic acid metabolites, especially PGD2, thus highlighting the therapeutic potential of sPLA2 inhibitors for stroke (Yagami, T. et al (2002) Mol. Pharmacol. 61, 114–126).
Most of the currently available PLA2 inhibitors such as scalaradial, BEL, AACOCF3 are molecules that are not suited for sustained biological intervention within the body. Moreover, the possibility of their generating antibodies that would neutralize the effect of the molecule are also significant. The need for an effective molecule that can inhibit the biological effect of secretory and/or cytosolic PLA2 is thus largely unmet.